1. Field of the Invention
The present invention relates to compositions for preventing and treating blood lipid level-related diseases comprising phenolic acid derivatives.
2. Description of the Related Art
Currently, coronary cardiovascular disease accounts for more than 30% of the total causes of death and become serious problems in advanced countries such as United States, Europe, etc. Also, heart diseases are tending to increase in developing countries due to westernization of dietary life, lack of exercise, etc. It is known that when the plasma cholesterol level is high, fat along with macrophages, foam cells, etc. is deposited on the wall of blood vessels to form plaque, causing arteriosclerosis, which blocks blood flow (Ross, R., Nature, 362, 801-809(1993)).
It has been reported that the plasma cholesterol level can be reduced by suppressing absorption of cholesterol. Acyl CoA-cholesterol-O-acyltransferase (ACAT) is an enzyme that converts cholesterol into cholesterol ester in the tissue of the human body. In experimental and clinical arteriosclerosis phenomenon, the formation of foam cells derived from macrophages or smooth muscle cells is a very important factor. The foam cells are formed by the action of ACAT and contain plenty of cholesterol ester transferred by LDL in the blood. Since the foam cells are frequently found on the wall of artery as the activity of ACAT increases, it is highly possible for ACAT inhibitor to act as an agent for preventing arteriosclerosis. Also, if the ACAT activity in the liver is suppressed, LDL-cholesterol level in the circulating blood may be lowered (Witiak, D. T. and D. R. Feller(eds), Antilipidemic Drugs: Medicinal, Chemical, and Biochemical Aspects, Elsevier, pp159-195(1991)).
Further, it has been reported that the plasma cholesterol level can be reduced by inhibiting the activity of cholesterol ester transfer protein (CETP) which mediates the cholesterol transfers between the lipoproteins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which is involved in the biosynthesis of cholesterol in the liver. HMG-CoA reductase mediates the synthesis of mevalonic acid, an intermediate in the biosynthesis of sterols or isoprenoids. Thus, the inhibition of this enzyme leads to the reduction of the rate of cholesterol biosynthesis, by which hypercholesterolemia can be effectively treated (William, W. P., Cardiovascular Pharmacology, Kanu Chatterjee(ed), Wolfe Pullishing, 8.6-8.7 (1994)). HMG-CoA reductase inhibitors commonly used are those derived from Penicillium sp. and Aspergillus sp., including Lovastatin™ and Simvastatin™ developed by Merck Co. (U.S.A.) and Pravastatin™ developed by Sankyo Co. (Japan). However, statins are known to induce an adverse side effect to the central nervous system (Saheki, A. T. et al., Pharm. Res., 11, 304-311 (1994)). Further, although Lovastatin and Simvastatin may reduce the plasma LDL cholesterol level by enhancing the activity of LDL receptor in the liver, they cause side effects such as increase in diverse enzymes including creatine kinase and rhabdomyolysis (Farmer, J. A. et al., Baillers-clin. Endocrinol. Metab., 9, 825-847 (1995)).
Meanwhile, the function of the liver is deteriorated by the excessive intake of fat-containing foods or alcohol, and infection of hepatitis B or C virus. Such conditions may develop into hepatitis, hepatic cirrhosis, liver cancer, etc. Particularly, the excessive intake of fat and alcohol through foods causes fatty liver wherein a large amount of lipids is deposited in the liver tissue and the levels of serum GOT (glutamate-oxaloacetate transaminase), GPT (glutamate-pyruvate transaminase) and γ GTP (γ-glutamyl transpeptidase) are elevated (T. Banciu, et al., Med. Interne., 20, 69-71(1982); and A. Par, et al., Acta. Med. Acad. Sci. Hung., 33, 309-319(1976)).
It has been reported by Hayashi et al. that an extract from green tea improved liver functions in a rat by preventing the elevation of serum GOT and GPT (M. Hayashi, et al., Nippon Yakuri gaku Zasshi, 100, 391-399(1992)).
The present inventors already discovered that bioflavonoids such as hesperidin, hesperetin, naringin and naringenin, and extracts of pericarp of citrus fruit abundantly containing the foregoings significantly reduce the plasma cholesterol level, inhibit the activity of ACAT, strongly inhibit the formation or accumulation of macrophage-lipid complex on the endothelial wall of an artery and have therapeutic and prophylactic effects of hepatic disease and filed applications for patent based on these discoveries (WO98/16220, WO098/16221, Korean Patent Application Nos. 98-10888 and 98-10889).
The present inventors also have studied phenolic acid derivatives, which is employed as a precursor in the biosynthesis of bioflavonoids and forms a backbone structure of bioflavonoids (W. Heller and G. Forkman, Biosynthesis of flavonoids, In the Flavonoids-Advanced in Research.(ed) J. B. Harborne, Chapman & Hall Co., London, 1993. pp 500-535), for the functions of the previous compounds. As a result it has been discovered that it can reduce plasma cholesterol level, inhibit the accumulation of macrophage-lipid complex on the arterial endothelium and prevent damage of liver cells and fatty liver and on the basis of this discovery, the present invention has been completed.